Clinical Development of Novel Drugs for Children with Refractory Cancers

作为药理学和实验治疗学(PET)组的一员，我参与了儿童癌症新药的开发，特别是新分子靶向药物的应用。该项目的主要目标是根据目前对人类癌症分子发病机制的理解，开发治疗儿童癌症的新药物，重点是更合理、更有针对性的药物开发方法。正在进行成人癌症临床开发的新的分子靶向药物将基于药物的作用机制和靶向在儿童癌症中的重要性而应用于儿童癌症。RAF激酶和受体酪氨酸激酶抑制剂索拉非尼的开发就是一个例子，用于儿童难治性癌症。MTOR通路参与人类癌症和1型神经纤维瘤病(NF1)相关肿瘤的进展，mTOR抑制剂的临床试验将在这两个患者群体中进行。此外，还将致力于治疗儿童癌症的新型细胞毒剂的临床开发，如抑制微管蛋白解聚的抗微管蛋白药物依沙比平(Epothilone B)类似物伊克沙比平(BMS-247550)。这些药物的药代动力学和药效学将被研究，并与成人的结果进行比较。甲氨蝶呤(MTX)救援剂羧基肽酶-G2(CPDG2)的开发将继续进行，直到FDA批准这种潜在的挽救生命的治疗方法。

As a member of the Pharmacology and Experimental Therapeutics (PET) Section I am involved in the development of new agents for childhood cancers, particularly the application of new molecularly targeted drugs. The primary objective of this project is to develop new agents for the treatment of childhood cancers with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. The development of the raf kinase and receptor tyrosine kinase inhibitor sorafenib for children with refractory cancers serves as an example. The mTOR pathway is involved in the progression of human cancers and neurofibromatosis type 1 (NF1) related tumors, and clinical trials with mTOR inhibitors will be pursued for both patient populations. In addition, the clinical development of novel cytotoxic agents for childhood cancers, such as the epothilone B analog ixabepilone (BMS-247550), an antitubulin agent, which inhibits tubulin depolymerization, will also be pursued. The pharmacokinetics and pharmacodynamics of these drugs will be studied and compared to results in adults. The development of the methotrexate (MTX) rescue agent carboxypeptidase-G2 (CPDG2) will be continued until FDA approval for this potentially life-saving treatment has been achieved.